Physically Dispersed, Molecularly Dissolved and/or Chemically Bound Drug(s) in an Empty, Hard Capsule Shell Composition

ABSTRACT

A hard shell capsule includes a body and a cap cooperatively defining a hollow core hard shell capsule. Each of the body and the cap has a composition that includes a polymer forming a hard polymer structure of the body and of the cap, at least one of the body and the cap composition including a therapeutically effective amount of a drug(s) loaded throughout the body and/or cap.

RELATED APPLICATIONS

This patent application is a continuation of and claims the benefit ofpending U.S. patent application Ser. No. 14/280,677 titled “PhysicallyDispersed, Molecularly Dissolved and/or Chemically Bound Drug(s) in anEmpty, Hard Capsule Shell Composition” filed May 19, 2014 which in turnis a continuation-in-part of and claims the benefit of U.S. patentapplication Ser. No. 12/841,008 titled “Physically/MolecularlyDistributed and/or Chemically Bound Medicaments In Empty, Hard CapsuleShells” filed Jul. 21, 2010 and issued as U.S. Pat. No. 8,728,521 on May20, 2014 which in turn is a continuation of and claims the benefit ofabandoned U.S. patent application Ser. No. 11/306,398 titled“Physically/Molecularly Distributed and/or Chemically Bound MedicamentsIn Capsule Shells” filed Dec. 27, 2005, each of the above-identifiedpriority applications and patents incorporated by reference as if fullyset forth herein.

FIELD OF THE DISCLOSURE

The disclosure relates to an improved or modified hard capsule shell,which is commonly used as a drug delivery system.

BACKGROUND OF THE DISCLOSURE

A drug is “a chemical substance used in the treatment, cure, prevention,or diagnosis of disease or used to otherwise enhance physical or mentalwell-being.

Medicament is a medicine or a substance used in a therapy. In thispatent application, the terms “drug” and “medicament” have been usedinterchangeably.

A combination drug therapy has been gaining a lot of importance inrecent times. The combination therapy in medicine involvesadministration of two or more therapeutically active ingredients. Theactive ingredient may be administered in a single dosage form or eachactive ingredient may be administered separately. The reasons of acombination therapy could be multiple—synergistic effects of drugs,reduction of side effect of the primary drug by an adjunct drug,avoidance of taking multiple tablets/capsules per day thereby savings onco-payment for different medicines and assurance of patient complianceto drug therapies.

In some embodiments of the combination drug therapy, the activeingredients are administered in a single dosage form. In thoseinstances, it is important to show that different drugs combined in thesame dosage form are stable during storage of the dosage form and shouldnot interact physically or chemically with other drugs or excipients toproduce degradation products. Also, each drug should show the desiredrelease rate from the dosage form to get absorbed in sufficientquantities upon oral administration or release the drug to surroundingenvironment in case of other delivery routes.

Pharmaceutical capsule dosage forms are widely used in delivering drugs.Composition is the combination of parts or elements and it is the way inwhich something is put together. The composition of the capsule shellconsists of a list of ingredients incorporated and their respectivequantities.

There are two main two types of capsules—hard shell capsules and softshell capsules.

Hard shell capsules, also called hard capsules herein, have two parts,the body and the cap. The body and the cap telescopically engage oneanother to define an interior volume of the hard capsule that typicallyholds dry ingredients, often in powder or granulated form. The body andthe cap of a hard capsule have sufficient rigidity that the body and capmay form “snap connections” that resist separation of the body and capafter telescopic engagement.

Some types of hard shell capsules are formed from compositions thatinclude polymers that have gelled or otherwise hardened and thereby forma polymeric system forming a hard polymer structure defining the shapeof the body and cap. Polymers used to form polymeric systems that canform hard polymer structures include, but are not limited to, gelatinsand carrageenans.

Soft shell capsules, also called softgels herein, are one piece,hermetically sealed shells often made of a gelatin, a plasticizer, andwater. The plasticizer softens the gelatin and makes it flexible andnon-rigid. A soft shell capsule typically holds an oil based liquid,suspension, or semisolid that does not dissolve the capsule's gelatin.

The term “hard” for a substance or matter is defined as a solid, firmsubstance or matter which is resistant to pressure and with anendurance.

Polymer is defined as a large molecule, or macromolecule, composed ofmany repeated subunits.

A system is defined as a set of connected things or parts forming acomplex whole.

A polymeric system means a system in which one of the major components(in terms of quantity and functionality) is a polymer.

A structure is the arrangement of and relations between the parts orelements of something complex. A structure has a form, shape,composition, formation or a constitution. A hard polymer structure isdefined as a rigid structure with polymer as a major component.

Hard capsule polymeric structure indicates a structure with a shape ofcapsule which is solid and does not change with time, external pressureand it has a polymer or a mixture of polymers as the major component. Ahard capsule has a body and cap. The cap is placed on the body andpressed to stay locked. In contrast, the soft polymer capsule structureis soft in nature and can change the shape by some pressure. Softcapsule shells have higher amounts of water/moisture compared to thehard capsule shell.

The manufacturing process for the hard and soft capsule shells arecompletely different. As mentioned earlier, in the case of hardcapsules, body and caps are prepared separately and are put together toform the entire capsule. Most of the soft capsules are prepared withgelatin. A solution of gelatin in water is prepared in a heated mixingtank. This also contains several excipients. In another tank, thefilling material containing medicines is prepared. The filling materialcan be a solution (liquid or semi-solid) or a suspension. During theencapsulation stage, the fill material and gelatin shell ribbon cometogether to form the softgel capsule. The capsules are dried to removeexcess moisture, but retain desired amount of moisture. In contrast,hard shell capsule shells contain significantly lower percent moisture.

The term “essential” means absolutely necessary. The hard shell capsulemust have some essential physical and chemical properties. Property of asubstance is a characteristics which helps to identify, describe, defineor quantify the substance. The capsule shell is thin. Empty capsulesshells are packed in big plastic bags and should not break duringtransportation and storage. After filling drugs, the capsules are storedin small bottles or in the blister packs. Capsule shells should notbreak during transportation and storage in these primary packagingsystems. For that, they should have sufficient elastic stiffness,tensile strength and should not be brittle. The drug incorporated in theshell matrix should not affect the essential physical and chemicalproperties. The shell matrix is expected to dissolve once reaching thestomach or if the capsule is enteric coated, should dissolve in theintestine. Some chemicals such as aldehydes are known to crosslinkgelatin. It slows down the dissolution of capsule shell. The drug shouldnot affect the desired dissolution rate of the capsule shell. If thedrug is hygroscopic, it may let capsule shell absorb more moisture thandesired. Higher moisture level in the hard capsule can make them soft.In the worst-case scenario, capsules can become sticky and adhere toeach other in the bottle.

The present disclosure relates to the hard capsule shell composition.The capsules are normally prepared using gelatin and other excipients.In recent times, several polymers have been employed to manufacture hardshell capsules. In 1977, Christen and Cheng patented (U.S. Pat. No.4,026,986) hard shell capsules manufactured using 2-hydroxyalkyl starch.It facilitated the production of shells and produced improved shells. WO1997004755 (International application PCT/EP1996/003263) prepared hardgelatin capsules with internal or external polymer coating using thedouble dipping technique. The inventors used polyvinyl alcohol andpolyvinyl acetate polymers along with necessary additives.

Gennadios invented non-gelatin capsules (U.S. Pat. No. 6,214,376)comprising k-carrageenan, water soluble plasticizer, and dextrins. Thecomposition also included hydrolyzed starch as a variation. U.S. Pat.No. 6,517,865 claimed hard and soft capsules comprising of water solublecellulose ethers, hydrocolloids and sequestering agents. The capsulesalso comprised of a coating with polymers including cellulose acetatephthalate, hydromellose phthalate etc.

In 2004 patent by Chen et al. (U.S. Pat. No. 6,752,953), authorsdescribed the usage of other polymers such as cellulose derivativesincluding cellulose, cellulose ester, methylcellulose, hydroxypropylmethylcellulose etc., acrylates including polyacrylate,polymethylacrylate, poly(methacrylate-methylmethacrylate) etc., andpolyolefins including polyethylene, polypropylene, polyvinyl chloride,polyvinyl alcohol etc. to prepare capsules. The inventors described aheat-melting method to prepare the capsule shells.

U.S. Pat. No. 8,029,821 used low-substituted cellulose ether to producehard capsules. The inventors also proposed a method for capsulepreparation. The pins were dipped in the alkaline solution oflow-substituted cellulose ether followed by dipping in an aqueous acidsolution to form a gel (low-substituted cellulose ethers are soluble inalkaline medium and form a gel in the acidic environment). The pinscovered with the gel were further washed with water before the dryingstep.

U.S. Pat. No. 6,949,256 used a mixture of kappa carrageenan and iotacarrageenan. Kappa carrageenan is known to form a strong gel in thepresence of potassium cations. However, these tend to be brittle andexhibit syneresis (exudating of liquid portion of the gel). Iotacarrageenan reacted with calcium cations and formed a weaker and moreflexible gel. In the U.S. Pat. No. 8,105,625, Rajewski and Haslamprepared hard shell capsules with pullulan, a plasticizer and adissolution enhancing agent. The capsules were meant to dissolve in themouth cavity (orally dissolving capsules).

US patent application #2008/0274187 prepared hard capsule compositionscomprising carrageenan, locust bean gum, xanthan gum, sorbitol, andpullulan. These capsules eliminated the problem of cracking,embrittlement, chipping and deformation due to water loss and mechanicalstress.

US patent application #2010/0168410 described a composition of hardcapsules of hydroxypropyl methylcellulose and the process of dip-coatingmanufacture. The dipping pins were heated at 55-95° C. and the polymersolution was maintained at 1 to 10° C. below its gelling temperature.

McConville et al. (Eur. J. Pharmaceutics & Biopharm. 57: 541-549 (2004))prepared a capsule filled with low-substituted hydroxypropyl cellulosein which a propanol tablet was placed followed by an erodible tabletcontaining HPMC and lactose manufactured by either direct and wetgranulation technique. In this case, the body of the capsule waspre-coated with insoluble ethyl cellulose suggesting the drug releaseonly after the dissolution of the cap of the capsule. In this case, thecapsule shell was not loaded with the drug—propranolol.

In the US patent application #2004/0146559, a film was formed on theinner surface of the capsule shell. The shell may have differentproperties to alter the drug release rates. In this patent, the core andthe shell were manufactured in situ. In the present disclosure, theempty hard capsule shell composition containing the drug may be producedby the manufacturers of empty capsules (such as, Capsugel, Universalcapsules, and Shionogi capsules).

In the U.S. Pat. No. 6,709,427, microspheres were encapsulated toproduce microcapsules. The core technology was to prepare microspheres.Microcapsule is a totally different kind of drug delivery techniquecompared to the hard capsule shell dosage form. In the hard capsuleshell dosage form, the drug granules or powder or microspheres arefilled in the capsule shell body on which the cap is fitted.

In the US patent application #2003/0104062, the capsules core was loadedwith the drug. The “capsule core” is the empty space within the capsuleshells and not the capsule shell composition. Hollow is defined as anempty space. A “hollow core hard shell capsule” means a hard shellcapsule with an empty space in the core. The shell surrounding thedrug-containing core governs the release rate (zero order) of the drugby diffusion mechanism due to its swelling. The shell also promotedgastric retention of the capsules by swelling upon the imbibition ofgastric fluid to a size that was retained in the stomach during the fedmode.

In the US patent application #2003/0104062, no drug was incorporated inthe capsule shell composition. In another embodiment, the drug wasincorporated in the shell so as to produce a burst effect. In this case,the same drug is incorporated in the core and in the shell/casing. Inthis patent, the preparation of capsule shell was part of themanufacturing process in situ. The desired zero order release, themanufacturing process and drug combination are the key differencesbetween US patent application #2003/0104062 and the current patentapplication.

U.S. Pat. No. 7,666,398 by Uhrich K described the composition and methodof preparation of a polymeric drug delivery system using polyanhydrides.Polyanhydrides linked low molecular weight drugs containing a carboxylicacid group and an amine, thiol, alcohol or phenol group within theirstructure. The inventors did not disclose the capsule as the drugdelivery system.

Yamamoto et al. in their U.S. Pat. No. 5,756,123 described a capsuleshell comprising of hydropropyl methylcelluse (HPMC), carrageenan as agelling agent and calcium or potassium ions as the co-gelling agent.Carrageenan helped to improve the shapability of HPMC. Co-gelling agentsassisted the gelation of carrageenan. Calcium ions were used foriota-carrageenan whereas potassium ions were used for kappa carrageenan.Carrageenan was not included in this composition as a therapeuticallyactive agent. But it was used as part of the polymer structure of thecapsule as a gelling agent to improve capsule properties.

Sakanishi et al in their US patent application #2006/0275361 describedrapidly dissolving gelatin compositions. Although gelatin iswater-soluble, it takes several minutes to dissolve in mouth to releasetheir core material. The inventors added dissolution enhancing materialsto the gelatin composition such as polyol plasticizer andwater-insoluble particulate components. Polyols were selected from thegroup consisting of glycerin, propylene glycol, sorbitol, maltitol,xylitol, mannitol, erythritol, isomalt, lactitol and combinationsthereof. One has to be very careful about understanding the definitionsof “capsule shell-forming composition” and “core composition” Gelatin,polyol and water-insoluble component formed a “capsule shell-formingcomposition” with which, the capsules were formed. The “corecomposition” was the one which was filled in the above-mentionedcapsules. The “core composition” may include sweeteners, flavors,medicaments and other excipients. The patent quoted, “Core materials mayinclude hydrophobic components, such as flavor oils or vegetable oils,as well as hydrophilic components”. Anyone knowledgeable in thepreparation of making capsules will agree that oils are not preferred inthe “capsule shell-forming composition”. The patent further quoted, “Thecore compositions, as previously mentioned, may take a variety ofphysical forms, such as powders, granules, gels, pastes or liquids”. Itwas clear that the inventors intended to fill their rapidly dissolvinggelatin capsules with the “core materials” prepared using the corecomposition, which included active medicaments. The inventors did notintend to add the “actives” in the “capsule shell-forming composition”.Also, the inventors did not teach to make capsules using polymericmaterials such as HPMC (hydroxypropyl methylcellulose).

There are mainly two methods to prepare capsules: pin dip-coating andheat-melting. A liquid mass is produced by dissolving the capsuleshell-forming compositions in a solvent system or by melting at anappropriate temperature. In the dip-method, plurality of pins maintainedat a certain temperature is dipped in the solution and is withdrawn at apre-determined rate while spinning. The pins coated with capsulecomposition are then dried at a gradual rate. The capsules (body andcap) are separated from the pins and are trimmed to an exact length. Themethod has been employed to prepare the body and cap of the capsules.The body and cap are joined or fitted together or cooperatively engagedand a logo is printed, if necessary.

InnerCap (http://www.innercap.com/) proposed combination capsules inwhich a capsule may contain another small capsule or a tablet along withgranules (multiphase, multi-compartment capsule technology). Thegranules may be made up of beads or other forms, which may contain morethan one type of drugs. This way, more than one type of drug may becombined in the same capsule. This is a different technology compared tothe current disclosure.

Soft gelatin capsules are another form of capsules in which a liquidcore material is filled. It has created a niche market of its own in thedrug delivery technology. In coming times, soft non-gelatin may beintroduced in the market due to advent of new polymeric systems.

BRIEF SUMMARY OF THE DISCLOSURE

The following are the key words used and the definition of various termsapplicable to this disclosure.

The present disclosure proposes a design to incorporate drug(s) in thecapsule shell-forming composition (body and cap). The term “drug(s)” isoptionally plural. It means one or more drugs may be incorporated in thecapsule shell-forming composition. Drugs in the compositions of cap andbody of the capsules may be the same or may be different. Othermedicaments in the form of granules, beads etc. can be filled in thecapsules, which are termed as “core materials”. Thus, the same capsulemay contain drugs in the core matrix and in the capsule shellcomposition.

There are two key phrases—“capsule shell-forming composition” and“capsule-core material/formulation”.

Capsule shell-forming composition described herein includes acomposition suitable for forming empty hard shell capsules. Capsuleshell-forming composition in this patent application comprises ofgelatin or a suitable polymer or a mixture of polymers, and suitableexcipients including plasticizer, coloring agent etc.

The term “comprising” or “comprises” is synonymous with “including”,“containing” and “characterized by”, is inclusive or open-ended. In someembodiments, drug/drugs may be added to the capsule shell-formingcomposition. The capsule shell-forming compositions may be different forcapsule cap and capsule body.

An “excipient” as used herein is more or less an inert substance addedas diluents or vehicles or to give form or consistency or properties.

Excipients may also act as a preservative. A “preservative” isunderstood herein to mean certain embodiments which are substances addedto inhibit chemical change or microbial growth. When the preservativeinhibits microbial growth, such preservatives may include, but are notlimited to sodium benzoate, methylparaben, propyl gallate BP, sorbicacid, chlorobutanol, dihydroacetic acid, monothioglycerol, potassiumbenzoate, propylparaben, benzoic acid, benzalkonium chloride,benzethonium chloride, benzyl alcohol, butylparaben, cetylpyridiniumchloride, ethylenediamine, ethylparaben, thimerosal and potassiumsorbate.

In certain embodiments, the capsule shell-forming composition may alsocontain an antioxidant. An “antioxidant” is understood herein to meancertain embodiments which are substances that inhibit oxidation. Suchantioxidants include, but are not limited to, asocorbyl palmitate,butylated hydroxyanisole, butylated hydroxytoluene, potassiummetabisulfite, and sodium metabisulfite.

In certain embodiments, the capsule shell-forming composition may alsocontain a flavoring agent. A “flavoring agent” is understood herein tomean certain embodiments which are substances that alter the flavor ofthe composition during oral consumption. A type of “flavoring agent”would be a sweetener. Preferred sweeteners can be natural or artificial.Flavoring agents can be chosen from a group commonly used in thepharmaceutical dosage forms.

In certain embodiments, the capsule shell-forming composition may alsocontain a buffering agent. A “buffering agent” is a weak acid or a weakbase or a mixture of two, which helps to prevent fluctuations in the pHof the medium when exposed to an acidic or basic environment. Some ofthe examples of “buffering agents” may be, but not limited to,phosphate, citrate, borate and acetate.

A “capsule dosage form” defined here as a delivery system for a drug(s)prepared with suitable materials such as gelatin or polymers to form acapsule shell and has a shape as depicted in FIG. 2.

A “capsule shell” is referred to as a film-forming composition used toencapsulate an active moiety in a capsule dosage form. For thisdisclosure, the capsule shell-forming composition also contains a drugor drugs.

A “medicament” is an agent that promotes recovery from an ailment or aninjury. Similar words to medicament are medicine, drugs, therapeuticagent and an active moiety.

The “therapeutically effective amount” is the amount of pharmaceuticalor nutraceutical substance that treats, totally or partially, a diseasestate or alleviates one or more symptoms of the condition.

The “empty, hard shell capsule” as name suggests is hard, durable andsmooth capsule. It retains its shape and it is dry in nature. As evidentfrom the word “empty”, there is nothing inside core portion of thecapsule shell when supplied by the capsule manufacturing company.Currently such “empty, hard shell capsule” compositions available in themarket do not contain any drug(s). The hard capsule shell comprises oftwo parts—a body in the core of which holds the contents of the dosageform (“capsule core formulation or capsule core material”), such as,powders/granules/beads/a tablet/a capsule and a cap, which fits on thebody of the capsule shell and acts as a cover (U.S. Pat. Nos. 4,510,168and 4,532,881).

The “capsule core material” may be prepared from a wide variety ofmaterials including, but not limited to, sweeteners, flavors,medicaments, coloring agents, dispersing agents, lubricants and glidantsetc. The “capsule core material” can be in the form of but not limitedto powder, granules, beads, pellets, microspheres, micro-capsules,mini-tablets and mini-capsules. Someone may argue that the body is typeof a core. However, people working in the field of pharmaceuticalformulations will not confuse the “body” of the capsule shell with thematerial within the core of the capsule.

The “drug-loaded empty, hard shells capsules” means the empty, hardcapsule shells in which a drug is loaded in the shell composition.

The term “loaded” means the drug is either physically dispersed ormolecularly dissolved in the shell composition or chemically bound tothe polymeric material incorporated in the capsule shell-formingcomposition.

The term “physically dispersed” in the above sentence means, the drug issuspended as a powder, crystals or granules in the capsule shell-formingcomposition. In other words, drug(s) is in an insoluble form in thecapsule-shell forming composition.

The term “molecularly dissolved” in the above sentence means, thedrug(s) is dissolved molecularly in the capsule shell-formingcomposition. Undissolved particles less than 200 nm particle size arenot visible to the naked eye and can be considered “dissolved”.

The term “chemically bound to the polymeric material” in the abovesentence means, the drug is ion-paired or complexed or covalently boundto the gelatin or polymer used to form the capsule shell. Thesedrug-loaded empty hard shell capsules are prepared by incorporating drugin the capsule shell-forming composition, which is then converted to acapsule shape (body and cap).

The key advantage of incorporation of drug(s) in the shell is to obtaina desired rate of release of the medicament, mainly for potent drugs.The rate of release will be controlled by the way in which the drug isembedded in the capsule shell-forming composition. Other advantage is toproduce a combination drug delivery system. The concept can be used forthe hard gelatin, hard non-gelatin, soft gelatin and soft non-gelatincapsules. The type of medicaments or drugs embedded in the capsuleshell-forming composition can be from any therapeutic class, but shouldbe of low-dose. The term “low-dose” is relative and in general, for thepurpose of this disclosure, it may be less than 50 mg of dose. The drughas to be stable in the capsule shell during manufacture and duringappropriate storage conditions for the capsules.

Other objects and features of the disclosure will become apparent as thedescription proceeds, especially when taken in conjunction with theaccompanying drawing sheets illustrating one or more illustrativeembodiments.

BRIEF DESCRIPTION OF FIGURES

FIG. 1 depicts a capsule cap which cooperatively engages in the capsulebody to form a hard shell capsule. FIG. 1 also shows the drug-loading inthe capsule cap. FIG. 1 shows loading of a single drug. But more thanone drug can be loaded in the capsule shell too.

FIG. 2 depicts a hard shell capsule in which the capsule cap iscooperatively engaged in the capsule body. In this figure, both thecapsule cap and body compositions are loaded with a drug. It also showsthe “core material” of the capsule, which contains a second drug filledinto the capsule.

DETAILED DISCLOSURE

In accordance with the present disclosure, FIG. 1 depicts a Capsule Cap1 that cooperatively engages a Capsule Body 2 to form a Hard shellcapsule 3 (see FIG. 2).

The Capsule Cap 1 in FIG. 1 has Medicament or Drug Molecules 4 dispersedthroughout between a Capsule Cap inner surface 5 and a Capsule cap outersurface 6. The Capsule Body 2 in the illustrated embodiment of the hardshell Capsule 3 has a similar structure, that is, a drug dispersedthroughout the Capsule Body 2 between inner and outer surfaces of theCapsule Body 2. The Shell Composition 7 of the Capsule Cap 1 or theCapsule Body 2 may consist of gelatin, HPMC, cellulose-derivatives,acrylates, polyolefins, vinyl polymers and other polymeric systems usedin forming Caps and Body of conventional hard shell capsules. The mainconstituent of the composition 7 of the capsule shell (body or cap) mayalso be a combination of polymers mentioned above. The Shell Composition7 (body or cap) may also contain other excipients such as plasticizers,emulsifiers, stabilizers, colorants, cross-linking agents etc. The rateof dissolution of capsule shell in a desired media or location withinthe body may be altered using appropriate capsule shell composition 7 asit is known in the art.

The Medicament or Drug 4 can be physically dispersed (insoluble form) ormolecularly dissolved (soluble form) throughout the Shell Composition 7of the Capsule Cap 1 or Body 2. Capsule core is depicted in FIG. 2 as 8.The Capsule Core is filled with Capsule Core Material 9. The Capsulecore material 9 may contain a drug or a combination of drugs along withexcipients. The Outer Surface of Capsule Cap 6 can be coated with 10 andthe Outer Surface of Body can be coated with 11. In some embodiments,the coating materials 10 and 11 may be the same and in some cases, thecoatings 10 and 11 may be different. In some cases, there may not be anycoatings 10 or 11. At the region where the Capsule Cap 1 fits on theCapsule body 2, in some embodiments, a Band 12 is placed to seal thegap.

The present disclosure proposes a new way of combining more than onedrug component in the capsule formulation. It may serve twopurposes—prevent/reduce drug-drug interaction during storage of thedosage form and the release rate of each drug may be controlled to adesired value. The drug-loaded empty hard capsule shells, in which theactive ingredient is physically dispersed or molecularly dissolved orchemically bound in the capsule shell, are then used further tomanufacture pharmaceutical capsule formulations by filling them withdrug-loaded powder, granules, beads, etc., i.e., the capsule corematerials. In one embodiment, the drug is dissolved in the capsuleshell-forming composition. In another embodiment, the drug which isinsoluble in the Capsule Shell-forming composition is physicallydispersed or suspended. In another embodiment, the drug may be partiallydissolved and partially suspended in the capsule shell-formingcomposition. For the purpose of this disclosure, partially is defined asmore than 10% of the total drug amount. For example, 30% drug may bephysically dispersed and 70% drug may be in the molecularly dissolvedform. In yet another embodiment, the drug is chemically bound to thegelatin or polymer used in the Capsule shell-forming composition. In yetanother embodiment, the drug is chemically bound to the gelatin orpolymer used in the capsule shell-forming composition and also dissolvedor suspended. The capsules are prepared by dip-coating or heat-meltingmethods.

The polymers that can be used in making the present hard capsule shellscan be divided into the following groups: 1) Cellulose- or cellulosederived-based material, which include, but are not limited to,cellulose, cellulose ether, methyl cellulose, hydroxypropyl methylcellulose, hydroxyproyl cellulose, hydroxyethyl cellulose, carboxymethylcellulose, cellulose acetate phthalate. 2) starch-based compounds, whichinclude, but not limited to hydroxyethyl starch, hydroxypropyl starch,hydroxyethyl methyl starch, 3) carrageenans—kappa and iota, 4) Acrylatederivatives which include, but not limited to, polyacrylate,polymethylacrylate, poly(acrylate-methylacrylate),poly(methylacrylate-methyl methacrylate), 5) polyolefins which include,but not limited to, polyvinyl chloride, polyvinyl alcohol, and polyvinylacetate and 6) pullulan (a polysaccharide polymer consisting ofmaltotriose units).

A hard capsule dosage form is manufactured by filling the core of thehard capsule shell with powders, granules, beads, pellets, a tablet,another capsule or combination thereof. In the recent times, scientistshave started to fill the hard capsule shells with liquids too. The hardcapsule shells are purchased from the capsule suppliers. There are mainthree manufacturers of hard capsule shells—Capsugel, Shionogi andUniversal Capsules. Each capsule has two parts—a body and a cap.Commonly used primary ingredients in the composition of the capsule bodyor the cap are gelatin and hydroxypropyl methyl cellulose. As mentionedin the earlier section, apart from gelatin, several new types ofpolymeric substances have been used to manufacture hard capsule shells.These are—cellulosic compounds, acrylates, starch ethers, polyolefins,pullulans, and carrageenans. Apart from the main constituent of thecapsule shell, gelatin or polymer, the shell may also contain otherexcipients such as plasticizers (e.g., polyethylene glycol, sorbitol,glycerol), stabilizers (antimicrobial and antioxidants), colorants (FD&Ccolors, titanium dioxide, natural dyes including riboflavin, carotenes,turmeric and caramel) and sequestering agents (citric acid, sodiumcitrate, ethylenediaminetetraacetic acid).

The rate of capsule dissolution in a desired media governs the releaseof medicaments residing in the core of the capsule. The rate of releasemay be altered using selected combination of polymers in the capsulecomposition or by a cross-linking of gelatin or polymer used in thecapsule shell formulation.

The present disclosure proposes a method to develop a combination dosageform in which the medicament resides in the core of the capsule andanother in the hard capsule shell composition itself. The medicament inthe hard capsule shell is either physically dispersed or molecularlydissolved or chemically bound to the gelatin or to the polymericmaterial of the capsule shell. In one embodiment, the body and the capof the capsule shell contain the same active moiety. In anotherembodiment, either the cap or the body of the capsule shell contains themedicament. In yet another embodiment, different medicaments areincorporated in the body and the cap. In yet another embodiment, acombination of medicaments is incorporated in the body and cap of thehard capsule shell compositions.

According to the present disclosure, the hard capsule shell manufacturermay manufacture the capsule shell compositions containing a drug(s) andsupply to a pharmaceutical company. The pharmaceutical company,purchasing the drug-loaded hard capsule shell compositions, will producea suitable composition (such as powders, granules etc.) of the corematerial containing different drug(s) and fill it in the drug-loadedcapsule shells.

There are various sizes of hard capsule shells available ranging from000 to 5, the most commonly used are sizes 0 and 1. The fill weight ofgranules with a density of 0.7 g/mL is 475 mg and 350 mg for size 0 and1 capsules, respectively. Size 000 capsule can contain 960 mg of corematerial loaded with medicament. The average weights of size 1 and 0empty hard gelatin capsule shell are 75 mg and 98 mg, respectively.These weights can vary, but overall the weights are low. The drugloading in the capsule shell composition can affect the properties ofthe capsule shell; and thus, the amount of drug loaded in the capsuleshell is limited. In general, only potent drugs can be loaded in capsuleshells.

Also, one skilled in the art will determine the stability of the drug inthe capsule shell composition during manufacture and storage. It isimportant to establish the desired release rate of medicament from thecapsule shell under pre-determined conditions such as in the acidic andbasic media, and in the presence of bile acids/food etc. The polymer forthe capsule shell and the drugs need to be selected judiciously.

Bioavailability of a drug constitutes of two features—the rate and theextent of absorption. For drugs with narrow therapeutic indices, it iscritical to maintain appropriate drug levels in the blood or tissues.For potent drugs, one must avoid dumping of drugs in a short period fromthe delivery device into the gastro-intestinal tract so that one canavoid erratic blood levels of the medicament.

The medicament, if insoluble, forms a suspension in the capsuleshell-forming composition. The medicament may dissolve in the capsuleshell-forming composition and in some cases, the medicament may form anion-pair bond with the groups in the polymer or the excipients used toprepare the capsule shell-forming composition. The medicament may form acovalent bond with the polymer or the excipients used to prepare thecapsule composition. The chemical bond can be of any nature—peptide, anamide, an ester or other kinds.

Overall, the drug may be present in the capsule-shell formulation inthree states—physically dispersed, molecularly dissolved and chemicallybound or combination of these.

In one embodiment, the drug may be in partially physically dispersed andmolecularly dissolved states in the capsule-shell composition. Inanother embodiment, the drug may be in partially physically dispersedand chemically bound states in the capsule shell composition. In yetanother composition, the drug may be in partially molecularly dissolvedand chemically bound states in the capsule-shell composition.

Upon administration of the hard shell capsule orally, it maydisintegrate or dissolve in the mouth cavity releasing the drug (s). Inanother embodiment, the capsule shell may stay intact in the mouthcavity and may dissolve or disintegrate in the stomach releasing thedrug(s). In another embodiment, the capsule shell may stay intact tillit reaches the intestinal tract and may dissolve/disintegrate in theintestine releasing the drug(s).

The release of drug, which is embedded in the capsule shell composition,may be controlled by three mechanisms—diffusion through the shellmatrix, hydrolysis of medicament-polymer chemical bond or by dissolutionof the hard capsule shell to release the drug. In an embodiment,multiple drugs can be incorporated in the capsule shell composition,which could be released with different mechanisms. In anotherembodiment, a laminated hard shell capsule is prepared using the doublepin-dip method. The drug-loaded polymer layer can be the inner or outerlayer. One such type of lamination could be enteric coating. Entericcoating is a special coating that prevents release of the drug(s) from adosage form until it reaches to the intestine.

Other medicaments may be placed in the capsule core in the form ofpowder, granules, beads, tablets, capsules etc. The concept can be moreclear or evident with the following examples.

Example 1: Entecavir (0.5 mq) in the Gelatin Capsule Shell and Tenofovir(300 mq) in the Core for the Chronic Hepatitis B Treatment

Entecavir and tenofovir are antiviral drugs used to treat hepatitis B.In a report by Petersen et al. (J Hepatol. 56(3):520-526, 2012), rescuetherapy with entecavir and tenofovir in CHB patients harboring viralresistance patterns or showing only partial antiviral responses topreceding therapies was observed to be efficient, safe, and welltolerated in patients with and without advanced liver disease.

In an embodiment, Entecavir (0.5 mg) may be physically incorporated insize 0 hard gelatin capsule shell by mixing entecavir in the gelatincapsule shell-forming composition. The particle size distribution ofentecavir will determine the dissolution rate of drug in the GI tractand thus, its absorption. Tenofovir pellets may be prepared usingconventional methods and the pellets equivalent to 300 mg of active maybe filled into the entercavir-loaded empty capsule shells.

Example 2: Clonidine (75 Microgram) in the Capsule Shell Composition andBupivacaine (10 mq) in the Core for Labor Pain

Polymer such as polymethacrylic acid (RCOOH) may be first converted toRCOCl form, which can react with clonidine in a suitable solvent system.The polymeric prodrug of clonidine may be dissolved in a suitable mediumalong with suitable excipients (plasticizer, coloring agent etc.) toform a solution. Hard capsule shells may be prepared using a pin-dipmethod known to those skilled in the art. Bupivacaine granules may beprepared using a conventional method and may be filled into theclonidine-loaded hard capsule shells. The dose of bupivacaine is 10 mgper capsule. Thus, in this case, bupivacaine may be released upondissolution of hard capsule shell and clonidine may be released afterthe hydrolysis of amide bonds.

Example 3: Ethinyl Estradiol (30 Microgram) and Drosperenone (3 mq) inthe Capsule Shell and Thalidomide (200 mq) in the Core

Teratogens are drugs that can cause birth defects by interfering withthe normal development of a fetus. Commonly known teratogensare—thalidomide, isotretinoin, tretinoin etc. If contraceptives arecoadministered with these teratogens, women taking these drugs willprevent accidental pregnancy and thereby birth defects.

In this case, ethinyl estradiol bears a phenolic hydroxyl group, whichcan form an ester bond with RCOOH (for example, with carboxymethylcellulose). The polymeric prodrug of ethinyl estradiol may be dissolvedin an aqueous system along with necessary excipients for the capsulecomposition. Drospirenone has very low water solubility (1.8 mg/L waterat 25° C.) and may be suspended in the capsule shell-forming solutionand hard capsule shells are manufactured using the pin-dip method.Thalidomide granules may be prepared using a conventional technique. Thegranules may be filled in the ethinyl estradiol/drospirenone-loadedcapsule shells to produce a combination dosage form.

Example 4: Omeprazole (10 mq) in the Capsule Shell and Pancrelipase(6000 to 24,000 USP Units of Lipase) in Core

Hard gelatin capsule shells may be prepared with physically andmolecularly distributing omeprazole (10 mg per capsule) in the capsuleshell-forming composition, which may be further coated with celluloseacetate phthalate (enteric coating). Spheres of 1 to 2 mm diameter ofpancrelipase may be prepared using conventional methods known to skilledin the art. For example, the spheres can be prepared using cetylalcohol, dimethicone, polyethylene glycol and triethyl citrate. Thespheres of pancrelipase may be filled in the omeprazole-loaded,enteric-coated hard capsule shells. Omeprazole and pancrelipaseformulations are typically enteric coated due to rapid degradation inthe acidic pH.

Example 5: Nabilone (1 mq) with Cyclophosphamide (50 mq)

In an embodiment, Nabilone, 1 mg, may be suspended in the gelatincapsule shell-forming composition. A chemotherapeutic agent,cyclophosphamide, 25 mg or 50 mg, granules may be prepared usingsuitable excipients and can be filled in the capsule shells withnabilone. Nabilone is a synthetic cannabinoid and has an excellentantiemetic property. Thus, it will reduce the nausea and vomiting causedby cyclophosphamide.

Other commonly used antiemetic agents such as, granisetron, ondansetron,metoclopramide etc. can be included in the capsule shell-formingcomposition. Several types of chemotherapeutic agents from classesincluding—Alkylating agents, Anthracyclines, Cytoskeletal disruptors(Taxanes), Epothilones, Histone Deacetylase Inhibitors, Inhibitors ofTopoisomerase I, Inhibitors of Topoisomerase II, Kinase inhibitors,Monoclonal antibodies, Nucleotide analogs and precursor analogs, Peptideantibiotics, Platinum-based agents, Retinoids, and Vinca alkaloids andderivatives, which can be delivered in the capsule dosage form, and canbe administered as a combination therapy using this platform.

Example 6: Naratriptan Hydrochloride (2.5 mq) in the Capsule Shell andNaproxen (500 mq) as the Core Material

Naratriptan hydrochloride, 1 to 2.5 mg, is used to treat migraine.Naproxen is a known to be effective against pain and inflammation.Naratriptan hydrochloride may be dissolved in the HPMC or gelatincapsule shell-forming composition to produce naratriptan-loaded capsuleshells. These capsules can be filled with the granules containingnaproxen (normal dose is 500 mg). Naratriptan is sensitive to acidic andalkali degradations. A suitable buffering agent may be used in thecapsule forming composition to maintain a neutral pH. Other triptansincluding almotriptan, eletriptan, rizatriptan and sumatriptan can alsobe used in the capsule shell-forming compositions.

Example 7: Probenecid, 500 mq as the Core Material and Colchicin, 0.5 mqin the Capsule Shell Composition

Probenecid prevents tubular reabsorption of urates thereby increasingurinary excretion of uric acid. This way, probenecid can be used toprevent gout attacks. Colchicine is also used prevent gout attacks.Thus, Probenecid and colchicine combination is used to treat gout orgouty arthritis.

There is only one approved colchicine product in the US market (Colcrys,0.6 mg by Takeda Pharma). Combination of probenecid and colchicine inthe tablet dosage form are marketed by Watson (brand) and Mirror Pharma.

In an embodiment, colchicine, 0.5 mg may be incorporated in thehydroxyethyl starch capsule shell-forming composition. Colchicinesolubility in water is 7 mg/mL. Hydroxyethyl starch is a biodegradableand water-soluble polysaccharide. Colchicine may be covalently bound tohydroxyethyl starch. The probenecid granules can be filled in thesecolchicine-loaded empty capsule shells.

Example 8: Vitamin B12 in the Capsule Shell and Metformin in the CapsuleCore

Almost 30% of people taking metformin face vitamin B12 deficiency. Inanother embodiment, Vitamin B12 may be dissolved in the HPMC or gelatincapsule shell-forming composition. These Vitamin B12-loaded capsuleshells may be filled with metformin granules. Such a combination willprevent Vitamin B12 deficiency in any patients taking metformin.

Example 9: Pramipexole Dihydrochloride (0.25 mq) in the Capsule ShellComposition and Sertraline (50 mq) as the Core Material

Pramipexole is known primarily for treating schizophrenia andparticularly for the treatment of Parkinson's disease. In the U.S. Pat.No. 6,255,329, a much better antidepressant activity was observed whenpramipexole was combined with another antidepressant agent. Sertralinewas one of the anti-depressant agent chosen. Other antidepressant may beused with pramipexole could be alprazolam, chlordiazepoxide,clomipramine, chinpirol, dibenzepin, doxepin, fluvoxamine, lofepramine,maprotiline, mirtazapine, mianserin, moclobemide, nefazodone,nortriptyline, opipramol, paroxetine, sulpiride, tranylcypromine,trazodone, trimipramine, tryptophan, venlafaxine and viloxazine. Thepatent described the following dosage forms for the delivery of suchcombinations—plain or coated tablets, lozenges, powders, solutions,suspensions, emulsions, syrups, suppositories etc.

In this example, pramipexole dihydrochloride, 0.25 mg, may be dissolvedin the capsule shell-forming composition, which can be converted topramipexole-loaded empty capsule shells. Sertraline, 50 mg, granules maybe filled in these pramipexole-loaded empty capsule shells.

Several drug such as tretinoin, isotretinoin, thalidomide and manyanti-cancer medicines can cause birth defects. It is advisable topostpone pregnancy while one is taking such medicines. In the followingexample, oral contraceptives are added in the capsule shell matrix.

Example 10

In this example, the cap of the capsules contain 0.03 mg of physicallydispered ethinyl estradiol and the body contains 0.15 mg of physicallydispered desogestrel. These capsules can be filled with one or more ofthe teratogenic medicines. It will prevent pregnancy during the therapy.

From the foregoing, it is clear that this disclosure opens up severalpossibilities using the drug-loaded hard capsule shell as a carrier ofdifferent medicaments along with a different set of drugs in the core.

While specific embodiments have been presented here, variousmodifications can be made and the disclosure is not limited to theexamples shown herein. Medicines may be incorporated in one of capsulebody or cap or medicines or may be incorporated in each of the capsulebody and cap. One may or may not fill the core with another drug. Thus,the empty drug-loaded capsule shell can also be used as a drug deliverysystem.

While one or more embodiments have been disclosed and described indetail, it is understood that this is capable of modification and thatthe scope of the disclosure is not limited to the precise details setforth but includes modifications obvious to a person of ordinary skillin possession of this disclosure, including (but not limited to) changesin material selection, size, operating ranges (temperature, volume,displacement, composition ingredients and ratios, and the like),environment of use, and also such changes and alterations as fall withinthe purview of the following claims.

What is claimed is:
 1. A hard shell capsule comprising: a body and a capcooperatively defining a hollow core hard shell capsule; each of thebody and the cap comprising a composition including a polymeric systemforming a hard polymer structure, at least one of the body and the capcomposition comprising a therapeutically effective amount of a drug(s)loaded throughout the polymeric system of said at least one of the bodyand cap, said polymeric system of said at least one of the body and capcomposition forming the hard polymer structure independently of thepresence or absence of the drug(s).
 2. The hard shell capsule of claim 1wherein the drug(s) is physically dispersed throughout the polymericsystem of said at least one of the body and the cap composition.
 3. Thehard shell capsule of claim 1 wherein the drug(s) is molecularlydissolved throughout the polymeric system of said at least one of thebody and the cap composition.
 4. The hard shell capsule of claim 1wherein the drug(s) is chemically bonded with the said polymeric systemof said at least one of the body and the cap composition.
 5. The hardshell capsule of claim 1 having no other drug in the capsule core. 6.The hard shell capsule of claim 1 comprising at least one drug disposedinside the capsule core.
 7. The hard shell capsule of claim 1 wherein afirst portion of the drug(s) is physically dispersed throughout the saidat least one of the polymeric systems of the cap and the bodycompositions, and a second portion of the drug(s) is chemically bondedthroughout with the said at least one of the polymeric systems of thecap and the body compositions.
 8. The hard shell capsule of claim 1wherein a first portion of the drug(s) is physically dispersedthroughout the polymeric system of the said at least one of the body andthe cap composition, and a second portion of the drug(s) is molecularlydissolved in the polymeric system of the said at least one of the bodyand the cap composition.
 9. The hard shell capsule of claim 1 whereinthe polymeric system of the said at least one of the body and the capcomprises at least one of the following: gelatin, hydroxypropylmethylcellulose, and carrageenan.
 10. The hard shell capsule of claim 1wherein the drug(s) of the said at least one of the body and the capcomposition does not affect the essential properties of the hard polymerstructure of said at least one of the body and the cap.
 11. A hard shellcapsule comprising: a body, a cap, a therapeutically effective amount ofa drug(s); the body and the cap cooperatively defining a hollow corehard shell capsule; each of the body and the cap comprising acomposition including a polymeric system forming a hard polymerstructure, and the drug(s) being present throughout the polymerstructures of the cap and the body compositions, said polymeric systemsforming the hard polymer structures independently of the presence orabsence of the drug(s).
 12. The hard shell capsule of claim 11 whereinthe drug(s) is physically dispersed throughout the cap and the bodycompositions.
 13. The hard shell capsule of claim 11 wherein the drug(s)is chemically bonded with the cap and the body compositions.
 14. Thehard shell capsule of claim 11 wherein the drug(s) is partiallyphysically dispersed and partially chemically bonded with the cap andthe body compositions.
 15. The cap and the body of the hard shellcapsule in claim 11 further comprising an enteric coating.
 16. The hardshell capsule of claim 11 having no other drug in the capsule core. 17.The hard shell capsule of claim 11 wherein said drug(s) comprise aplurality of different drugs disposed inside the capsule core.
 18. Thehard shell capsule of claim 11 wherein a first portion of the drug(s) isphysically dispersed throughout the polymeric systems of the cap and thebody compositions, and a second portion of the drug(s) is molecularlydissolved in the polymeric systems of the cap and the body compositions.19. The hard shell capsule of claim 11 wherein the polymeric systems ofthe body and the cap each comprise at least one of the following:gelatin, hydroxypropyl methylcellulose, and carrageenan.
 20. The hardshell capsule of claim 11 wherein the drug(s) do not affect theessential properties of the hard polymer structures of the body and thecap.